Phase 1/2 study of mRNA-4359 administered alone and in combination with immune checkpoint blockade in adult participants with advanced solid tumors.
Authors: John D. Powderly, Ryan J. Sullivan, Martin Gutierrez, Adnan Khattak, Sajeve Samuel Thomas, Antonio Jimeno, Stephanie Pascarella, Lili Zhu, Manju Morrissey, Robert S. Meehan, Ferdous Barlaskar, Michelle Brown, David R. Spigel
Journal: Journal of Clinical Oncology (2023)

TPS2676 Background: mRNA-4359 is a lipid nanoparticle encapsulated mRNA-based cancer vaccine encoding for concatemerized program death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) antigens given as an intramuscular injection. These proteins are found across a wide range of cancer types. PD-L1 is a cell surface receptor expressed on both tumor and regulatory immune cells and functions as a checkpoint to inhibit T cell function, while IDO1 is an L-tryptophan metabolizing enzyme involved in T cell suppression and immune tolerance. Both are thought to impart an inhibitory tumor microenvironment which allows tumor cells to escape immune monitoring and clearance. T cells that can target PD-L1 and IDO1 are known to pre-exist in cancer patients and a recent study leveraging a peptide-based vaccine approach demonstrated they can be induced to elicit clinically meaningful and durable tumor responses in patients with metastatic melanoma when combined with PD-1 inhibition. mRNA-4359 encodes immunogenic peptides proposed to generate anti-PD-L1/IDO1-specific T-cells to kill immunosuppressive regulatory cells as well as cancer cells which express those antigens and thus tip the balance towards an inflammatory and/or immune permissive tumor microenvironment. Additionally, combination with checkpoint inhibition may further amplify this anti-tumor immunostimulatory effect, resulting in superior clinical outcomes. Methods: The primary objective of this first in human, open label Phase 1/2 study is to assess safety and tolerability, with secondary objectives to measure T cell profile changes and initial anti-tumor activity. Arm 1a entails dose escalation of mRNA-4359 monotherapy with dose levels guided by a modified continual reassessment method in participants with locally advanced/metastatic cancers, including cutaneous melanoma, non-small cell lung cancer (NSCLC), non-muscle invasive bladder cancer, head/ neck squamous cell carcinoma, microsatellite stable colorectal cancer, basal cell carcinoma or triple negative breast cancer. Arm 1b will be dose confirmatory and will run concurrently with a pharmacodynamic arm; both will assess mRNA-4359 in combination with pembrolizumab in patients with primary/secondary checkpoint inhibitor refractory locally advanced/metastatic melanoma or NSCLC. The totality of available data from these arms will be used to support determination of a recommended phase 2 dose. Arm 2 includes two single arm expansion cohorts evaluating mRNA-4359 in combination with pembrolizumab therapy in patients who have not received any prior therapy for their cancer in this setting of locally advanced/metastatic melanoma (Cohort 1) or locally advanced/metastatic NSCLC with PD-L1 TPS of ≥ 1% (Cohort 2). Study enrollment into Arm 1a has commenced in the United States and Australia with plans to open sites in Europe later in 2023. Clinical trial information: NCT05533697 .